MECHANISMS OF INSULIN RESISTANCE IN HUMAN OBESITY - EVIDENCE FOR RECEPTOR AND POSTRECEPTOR DEFECTS
MECHANISMS OF INSULIN RESISTANCE IN HUMAN OBESITY - EVIDENCE FOR RECEPTOR AND POSTRECEPTOR DEFECTS
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DOI：
10.1172/jci109790
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发表时间：
1980-01-01
影响因子：
15.9
通讯作者：
OLEFSKY, JM
中科院分区：
文献类型：
--
作者：
KOLTERMAN, OG;INSEL, J;OLEFSKY, JM
采用改良的正常血糖葡萄糖钳夹技术，测定了7名正常人和13名肥胖者体内胰岛素-葡萄糖处置剂量-反应曲线的形状。每名受试者在胰岛素输注速率分别为每分钟15、40、120、240或1200亩[单位]的情况下，至少进行3次正常血糖研究。与对照组相比，所有肥胖受试者的葡萄糖处理率均降低(101。+-)。16对186。+-。胰岛素输注40mU/m2/min，16 mg/m~2/min。肥胖受试者的平均剂量-反应曲线右移，即半数最大有效胰岛素浓度为270。+-。肥胖者为27微U/毫升，而肥胖者为130微U/毫升。对照为10微U/毫升。在9名肥胖受试者中，剂量-反应曲线右移，最大葡萄糖处置速率(在最大有效胰岛素浓度时)显著降低，表明受体和受体后都有缺陷。4名肥胖患者的剂量-反应曲线右移，但达到了正常的最大葡萄糖处置速率，这与胰岛素受体下降是唯一的异常一致。当对个体数据进行分析时，最低胰岛素血症、最不胰岛素抵抗的患者只显示受体缺陷，而最高胰岛素血症的患者表现出最大的受体后缺陷，这表明随着患者从轻度胰岛素抵抗发展到严重胰岛素抵抗，缺陷的频谱是连续的。当评估S抑制肝脏葡萄糖输出的胰岛素能力时，高胰岛素血症在所有受试者中都产生了完全抑制。肥胖受试者的剂量-反应曲线右移，表明胰岛素受体存在缺陷。肥胖者分离的脂肪细胞与胰岛素的结合量减少，胰岛素结合量与半最大刺激和葡萄糖处理所需的血清胰岛素浓度呈极显著负相关。在所有受试者中，细胞胰岛素受体减少导致与肥胖相关的胰岛素抵抗；在最不高胰岛素血症、胰岛素抵抗的患者中，胰岛素受体减少是唯一的缺陷，而在更高胰岛素血症、胰岛素抵抗的患者中，胰岛素抵抗是受体和受体后异常共同作用的结果；所有肥胖患者对胰岛素不敏感，S抑制肝脏葡萄糖输出的作用；这完全是胰岛素受体减少的结果；这种胰岛素效应中没有受体后缺陷的表现。
Using a modification of the euglycemic glucole clamp technique, the shape of the in vivo insulin-glucose disposal dose-response curves in 7 control and 13 obese human subjects was determined. Each subject had at least 3 euglycemic studies performed at insulin infusion rates of 15, 40, 120, 240, or 1200 mU[units]/M2 per min. The glucose disposal rate was decreased in all obese subjects compared with controls (101 .+-. 16 vs. 186 .+-. 16 mg/M2 per min) during the 40 mU/M2 per min insulin infusion. The mean dose-response curve for the obese subjects was displaced to the right, i.e., the half-maximally effective insulin concentration was 270 .+-. 27 .mu.U/ml for the obese compared with 130 .+-. 10 .mu.U/ml for controls. In 9 of the obese subjects, the dose-response curves were shifted to the right, and maximal glucose disposal rates (at a maximally effective insulin concentration) were markedly decreased, indicating both a receptor and a postreceptor defect. Four obese patients had right-shifted dose-response curves but reached normal maximal glucose disposal rates, consistent with decreased insulin receptors as the only abnormality. When the individual data were analyzed, the least hyperinsulinemic, least insulin-resistant patients displayed only the receptor defect, whereas those with the greatest hyperinsulinemia exhibited the largest post-receptor defect, suggesting a continuous spectrum of defects as one advances from mild to severe insulin resistance. When insulin''s ability to suppress hepatic glucose output was assessed, hyperinsulinemia produced total suppression in all subjects. The dose-response curve for the obese subjects was shifted to the right, indicating a defect in insulin receptors. Insulin binding to isolated adipocytes obtained from the obese subjects was decreased, and a highly significant inverse linear relationship was demonstrated between insulin binding and the serum insulin concentration required for halfmaximal stimulation and glucose disposal. Decreased cellular insulin receptors contribute to the insulin resistance associated with human obesity in all subjects; in the least hyperinsulinemic, insulin-resistant patients, decreased insulin receptors are the sole defect, whereas in the more hyperinsulinemic, insulin-resistant patients, the insulin resistance is the result of a combination of receptor and postreceptor abnormalities; all obese patients were insensitive to insulin''s suppressive effects on hepatic glucose output; this was entirely the result of decreased insulin receptors; no post-receptor defect in this insulin effect was demonstrated.